Vascular disease is the major cause of morbidity and mortality in diabetes. Two types have been defined--microvascular disease affecting predominantly the eye and kidney and macrovascular disease (atherosclerosis) affecting both peripheral and coronary arteries. To study the pathogenesis of these disorders, relevant functional, morphological and metabolic parameters will be compared in animal models with diabetes and in in vitro systems. Particular emphasis will be placed on studying the normal metabolism and function of the vascular wall and its components and delineating how they are altered in diabetes. These studies will utilize cultured endothelial and smooth muscle cells, isolated capillaries, and segments of large arteries from control and diabetic animals. Among the areas to be studied are cell motility and growth, the metabolism of fuels and connective tissue and prostaglandin synthesis. In addition the biological effects of insulin will be assessed as will the nature of the insulin receptor in endothelial and smooth muscle cells. We will also attempt to study the pathogenesis of macrovascular disease in the rabbit, and animal model in which diabetes has so far been shown to lessen the severity of atherosclerosis for reasons unknown. Several potential atherogenic factors will be assessed including circulating lipoproteins and platelets, the metabolism of lipids and liproteins by the arterial wall, and the severity of diabetes. Finally, one of the projects will evaluate a morphometric method for studying the natural history of diabetic microangiopathy. This work will be carried out in man and will utilize a unique population of identical twins, some concordant and some discordant for diabetes. The studies in this program should provide important insights into the pathogenesis of macrovascular and microvascular disease in diabetes. They will also, hopefully, provide a groundwork for devising approaches for preventing these complications.